Skeletal muscle is the primary pathway of glucose disposal in the body through glucose uptake, storage as glycogen, and/or oxidation. Hence the development, progression and treatment of type 2 diabetes (T2D) are intimately related to the regulation of energy metabolism in muscle. We propose to apply iterative computational modeling in conjunction with both in vitro and in vivo experimentation to uncover the integrated control of energy metabolism in muscle and determine how its regulation is altered in disease (T2D). We will develop computer models of muscle energy metabolism by utilizing the substantial foundation of software and data resources that we have established. Models will be parameterized and validated based on kinetic time- course experiments using purified mitochondria and in vivo 31P-magnetic resonance spectroscopy. Data will be obtained from male Wistar rats (normoglycemic) and the Goto Kakizaki rat model of T2D (hyperglycemic) to identify functional differences between these groups. We will determine how whole body glucose disposal is altered in T2D by coordination of the pathways of glucose and fatty acid uptake and disposal (glycogen synthesis, glycogenolysis, fatty acid oxidation, TCA cycle, and oxidative phosphorylation) using experimental protocols defined by the modeling effort. Our goal is to quantitatively describe and understand the regulation of skeletal muscle oxidative metabolism in both healthy and T2D animals. Furthermore, thorough understanding of the mechanism of action of exercise, the putative targets influenced by exercise may generate new approaches to prevention of the disease and potentially identify new targets for diabetes treatment. PUBLIC HEALTH RELEVANCE: Relevance: We propose to use computer simulation of the biochemical processes involved in glucose uptake and utilization in muscle to uncover mechanistic dysfunction that arises in the early stages of type 2 diabetes. By determining and validating novel mechanisms that impair the ability of muscle to dispose of glucose, we will attain fundamental new insights into how this disease and how its progression might be slowed or even reversed.